The long-range goal of these studies is to develop a parenteral vaccine delivery system utilizing the principles of controlled-release which will be sufficiently safe for routine immunization of children and adults. During the next four years we will develop controlled-release vaccines using as model systems four vaccine antigens each of which is currently recommended for routine childhood immunization: 1) a purified soluble protein antigen, tetanus toxoid 2) a protein - polysaccharide conjugate, H influenzae b polysaccharide - tetanus toxoid conjugate 3) a viral subunit vaccine, Hepatitis B surface antigen 4) a whole bacterial cell, Bordetella pertussis vaccine. We will prepare and evaluate controlled release preparations of each vaccine with the aims of: 1) enhancing the quantity, quality and persistence of the antibody response 2) reducing local and systemic reactions 3) reducing the number of doses required to induce and maintain a protective antibody response and 4) reducing the total quantity of antigen required to induce and maintain the antibody response. The results of these studies win enable us to initiate human trials with one or more of these vaccine preparations within 3 or 4 years. The primary approach will be to encapsulate each vaccine antigen in injectable microspheres prepared from a biodegradable polymer. The polylactic acid/glycolic acid polymer system will be used preferentially because of its long track record of safety in human use as resorbable suture materia. In order to solve specific problems, other polymer systems or mixtures of polymer systems may be tried, including: 1) tyrosine based iminocarbonates to provide intrinsic adjuvant activity 2) polyanhydrides to provide a water impermeable matrix to improve control over antigen release and to improve vaccine stability in vivo. 3) microencapsulated liposomes to avoid the denaturing effects organic solvents on labile antigens 4) non-ionic block copolymers added to the PLAGA system, to control release kinetics and to provide intrinsic adjuvant activity. For each controlled-release preparation we will evaluate antigen release kinetics in vitro, antigenicity of released antigen, and immunogenicity in standardized murine and guinea pig models of vaccine potency using aluminum adjuvanted and fluid vaccine as controls. Controlled release preparations which show promise will be evaluated further to determine the mechanism of enhanced immunogenicity, to monitor the physical and metabolic fate of the microcapsules and vaccine antigen and to evaluate the safety.